Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Marzioni, M; Saccomanno, S; Agostinelli, L; Rychlicki, C; De Minicis, S; Pierantonelli, I; Trauner, M; Fickert, P; Müller, T; Shanmukhappa, K; Trozzi, L; Candelaresi, C; Baroni, GS; Benedetti, A.
PDX-1/Hes-1 interactions determine cholangiocyte proliferative response to injury in rodents: possible implications for sclerosing cholangitis.
J Hepatol. 2013; 58(4):750-756
Doi: 10.1016/j.jhep.2012.11.033
Web of Science
PubMed
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FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Fickert Peter
- Trauner Michael
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- Abstract:
- Cholangiocyte proliferation plays a role in the progression of cholangiopathies, in particular in primary sclerosing cholangitis. The mechanisms regulating cholangiocyte proliferation are still undefined. Pancreatic Duodenal Homeobox protein 1 (PDX-1) is expressed by reactive cholangiocytes. In the adult pancreas, PDX-1 regulates the proliferative response to injury of ductal cells. Its effects can be counteracted by Hairy and enhancer of split 1 (Hes-1). We aimed at studying whether PDX-1/Hes-1 interactions regulate cholangiocyte proliferation in response to injury. The effect of the loss of PDX-1 on cholangiocyte proliferation was studied in vitro. In vivo PDX-1-heterozygous (+/-) mice were subjected to either DDC feeding (a model of sclerosing cholangitis) or to bile duct ligation (BDL). PDX-1/Hes-1 interactions on cell proliferation were determined by exposure to All-trans Retinoic Acid (At-RA), an inductor of Hes-1. In vitro, cholangiocyte proliferation was undetectable in cells pre-treated with PDX-1 siRNA. In vivo, increases in bile duct mass and collagen deposition observed after DDC feeding or BDL were significantly reduced in PDX-1(+/-) mice. Hes-1 expression is reduced in proliferating cholangiocytes; At-RA induced a dose-dependent increase in Hes-1 and a decrease in PDX-1 expression. At-RA neutralized the increases in PDX-1 expression and cell proliferation, both in vitro and in vivo in DDC mice. PDX-1 is overexpressed and Hes-1 downregulated in cholangiocytes isolated from PSC livers. Hes-1 downregulation allows PDX-1 to act as a major determinant of cholangiocyte proliferation in response to cholestatic injury. These findings provide novel mechanistic insights into the pathophysiology of cholangiopathies. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism
- Biliary Tract - injuries Biliary Tract - metabolism Biliary Tract - pathology
- Cell Proliferation -
- Cells, Cultured -
- Cholangitis, Sclerosing - etiology Cholangitis, Sclerosing - metabolism Cholangitis, Sclerosing - pathology
- Disease Models, Animal -
- Gene Expression -
- Heterozygote -
- Homeodomain Proteins - genetics Homeodomain Proteins - metabolism
- Humans -
- Mice -
- Mice, Knockout -
- RNA, Messenger - genetics RNA, Messenger - metabolism
- RNA, Small Interfering - genetics
- Trans-Activators - deficiency Trans-Activators - genetics Trans-Activators - metabolism
- Find related publications in this database (Keywords)
- Cholangiocyte
- Proliferation
- Primary sclerosing cholangitis
- PDX-1